Malaria is one of the most common infectious diseases and an enormous public health problem. The disease is caused by protozoan parasites of the genus Plasmodium, including the most serious form of the disease caused by Plasmodium falciparum. Malaria is also caused by Plasmodium berghei. Although some are under development, no vaccine is currently available for malaria that provides a high level of protection; preventive drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are often too expensive for most people living in endemic areas. Malaria infections are often treated through the use of antimalarial drugs, such as quinine or artemisinin derivatives. However, the parasites have evolved to be resistant to many of these drugs. Therefore, in some areas of the world, only a few drugs remain as effective treatments for malaria.
Tuberculosis (abbreviated TB for tubercle bacillus) is a common and often deadly infectious disease caused by mycobacteria. In humans, TB is caused mainly by Mycobacterium tuberculosis. One-third of the world's current population has been infected with M. tuberculosis, and new infections occur at a rate of one per second. The proportion of people in the general population who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing. Compounding the impact of this disease is the emergence of resistant strains of TB.
Mycobacterium avium complex (MAC) is a group of genetically related bacteria belonging to the genus Mycobacterium. It includes Mycobacterium avium subspecies avium (MAA), Mycobacterium avium subspecies hominis (MAH), and Mycobacterium avium subspecies paratuberculosis (MAP). Historically, MAC has also included Mycobacterium avium intracellulare (MAI)—a distinct species of bacteria. Treatment involves a combination of anti-tuberculosis antibiotics, which include:Rifampicin, Rifabutin, Ciprofloxacin, Amikacin, Ethambutol, Streptomycin, Clarithromycin, and Azithromycin. Resistance to current therapies is also an issue related to MAC. M. avium complex (MAC) infection is a serious health concern for AIDS patients. Standard treatment regimens consist of clarithromycin (CLA), ethambutol and a rifamycin. Treatment failure has been reported. Without being bound by theory, it is believed herein that the failure may be due to the emergence of CLA-resistance.
M. avium complex (MAC) infection is a serious health concern for patients living with AIDS, who numbered an estimated 34.4 million people world-wide in 2008. MAC is the causative agent for more than 90% of the non-tuberculous mycobacterial infections in these patients. Standard treatment regimens consist of clarithromycin (CLA), ethambutol and a rifamycin. Though macrolide antibiotics are known to be useful for treating infections such as respiratory tract and soft tissue infections, macrolides have been reported to have poor activity against these diseases.
It has been surprisingly discovered that fluoroketolide macrolides, such as those of the formula I are useful against the infectious pathogens mycobacterium avium complex, mycobacterium tuberculosis, plasmodium falcium, Narcadia, and plasmodium berghei, and diseases caused by those pathogenic organisms, including but not limited to tuberculosis, malaria, including severe malaria and chronic malaria, MAC diseases, such as Hot Tub Lung, Lady Windermere syndrome, and diseases present in immuno-compromised patients, such as senior citizens and those suffering from HIV or cystic fibrosis, and the like.
Described herein are compounds, compositions, formulations, and methods for treating patients with mycobacterium avium complex, mycobacterium tuberculosis, plasmodium falcium, or plasmodium berghei, infection. The compositions, formulations, and methods include a therapeutically effective amount of a macrolide and/or ketolide compound described herein.
In one illustrative embodiment of the invention, compounds, compositions, formulations, and methods are described herein for treating patients with MAC infections, including immunocompromised patients, such as patients with HIV, with MAC infections. In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with MAC infections that are caused at least in part by macrolide resistant organisms, including MAC infections caused at least in part by CLA-resistant organisms. The compositions and formulations include a therapeutically effective amount of one or more compounds and/or compositions described herein. The methods include the step of administering a therapeutically effective amount of one or more compounds and/or compositions described herein to the patient.
In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with malaria. In another embodiment, compounds, compositions, formulations, and methods are described herein for prophylactically treating patients with malaria. In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with malaria caused at least in part by resistant organisms, including resistant P. vivax, P. falciparum, and/or caused at least in part by macrolide resistant organisms, such as azithromycin-resistant organisms. The compositions and formulations include a therapeutically effective amount of one or more compounds and/or compositions described herein. The methods include the step of administering a therapeutically effective amount of one or more compounds and/or compositions described herein to the patient.
In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with tuberculosis. In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with tuberculosis that are caused at least in part by macrolide resistant organisms, including XRD tuberculosis. In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with dormant forms of tuberculosis. The compositions and formulations include a therapeutically effective amount of one or more compounds and/or compositions described herein. The methods include the step of administering a therapeutically effective amount of one or more compounds and/or compositions described herein to the patient.
In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with pulmonary nocardiosis, including immunocompromised patients, such as patients with HIV, with nocardiosis. In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with pulmonary nocardiosis. In another embodiment, compounds, compositions, formulations, and methods are described herein for treating patients with cutaneous nocardiosis. The methods include the step of administering a therapeutically effective amount of one or more compounds and/or compositions described herein to the patient. The compositions and formulations include a therapeutically effective amount of one or more compounds and/or compositions described herein.